Expanding the Therapeutic Horizon of Sodium Glucose Co-transporter-2 Inhibitors in Acute Kidney Injury

In large randomized trials of adults with chronic kidney disease (CKD), sodium glucose co-transporter-2 (SGLT2) inhibitors have been shown to substantially slow progression of kidney disease (meta-analysis primary outcome: relative risk [RR], 0.63; 95% confidence interval [CI], 0.58-0.69) and reduce the risk of acute kidney injury (AKI) by around a quarter (prespecified secondary outcome: RR 0.77; 95% CI, 0.70-0.84).1 Additionally, SGLT2 inhibitors have significant beneficial effects on the risk of the composite of cardiovascular death or hospitalization for heart failure in the studied populations with diabetes, heart failure, or CKD (prespecified secondary outcome: RR, 0.77; 95% CI, 0.74-0.81).1 Historically, evidence supporting SGLT2 inhibitor use in kidney transplant recipients has been limited because of concerns about the potential negative impact on graft function and increased risk of urinary tract infections. However, a recent meta-analysis of 3856 kidney transplant recipients published in July’s edition of Transplantation demonstrated cardiorenal benefits and a risk of overall urinary tract infection incidence comparable with that seen in the nontransplant population, reinforcing the therapeutic potential of this important class of drug in kidney transplant recipients.2 In this preclinical study, Yamanoi et al3 explore a novel mechanism by which dapagliflozin protects against ischemia/reperfusion injury (IRI), a major cause of AKI in hospital settings. Using multiphoton intravital imaging in a nondiabetic mouse model, they demonstrate that dapagliflozin significantly reduces neutrophil infiltration into renal microvasculature during early reperfusion. This effect is at least partially mediated by enhanced adenosine 2A receptor signaling, as shown by the partial reversal of benefit with receptor antagonism. Dapagliflozin also downregulated key proinflammatory mediators, suggesting attenuation of vascular inflammation. Metabolome analysis revealed a shift toward enhanced tricarboxylic acid cycle activity, reduced glycolysis, and increased adenosine generation, together pointing to a form of metabolic reprogramming that supports anti-inflammatory and cytoprotective pathways. The authors’ translational perspective is timely and compelling, potentially offering new avenues to mitigate ischemic AKI in diverse clinical contexts. Importantly, these preclinical insights align with the aims of the ongoing RENAL-LIFECYCLE trial, which is investigating the long-term efficacy and safety of SGLT2 inhibitors in kidney transplant recipients.4 The findings reported here shed new light on how SGLT2 inhibition affects the kidney during IRI and suggest interesting new directions for future study of this drug class. MECHANISTIC INSIGHTS Although the existing clinical data provide strong evidence for SGLT2 inhibition in managing CKD, in reducing AKI in chronically treated patients, and more specifically for the generalizability of these effects to the transplant population, there is currently little understanding of the mechanism by which the beneficial effects on AKI occur. This is important when considering the use of these medications around the time of transplant, as an understanding of the mechanism by which they are acting might help us to select a population and dosing strategy to evaluate clinically. In a transplant setting, and with delayed graft function as a target, we could choose to treat the donor, the organ ex situ, or the recipient. We could also choose to treat patients prophylactically, or only those with established delayed graft function. Interestingly, previous studies using MRI to evaluate the acute and chronic effects of SGLT2 inhibition on renal oxygenation have found no difference between treatment and control groups,5 suggesting that the effect on AKI is not mediated by improving parenchymal oxygen delivery; however, before this study, there was little information available on what the underlying mechanism might be. Here, the authors show that 7 d of pretreatment with dapagliflozin were protective against IRI-induced AKI in a mouse model, which is concordant with previous clinical observations. They use an elegant in vivo imaging method, which they have previously reported in this journal,6 to show that this appears to be due at least in part to decreased neutrophil extravasation. This is itself dependent on enhanced adenosine signaling via the 2A receptor, which is well characterized as an important modulator of the innate immune response, including in the setting of renal IRI.7 Pretreatment with dapagliflozin increased the amount of adenosine found in biopsies taken from mouse kidneys exposed to IRI, which decreased matrix metalloproteinase-9 activation, and this is hypothesized to underly the improvement in renal function seen in the treatment group. Partial reversal of these effects by co-administration of an adenosine 2A receptor antagonist strongly supports this hypothesis. The authors have therefore shown, for the first time, that enhanced adenosine signaling in the innate immune compartment underlies at least part of the beneficial effect of SGLT2 inhibition on post-IRI AKI. FUTURE DIRECTIONS These new findings suggest a number of avenues for future study. The authors identify that in the context of transplantation, both donor and recipient pretreatment may confer benefit, and these strategies need to be investigated in a transplant-relevant model. Administration during the donor management phase is attractive, and an ongoing multicenter UK trial treating donors declared dead by neurological criteria with simvastatin provides precedent for this approach.8 However, ethical considerations limit treatment administered to the donor for the benefit of the future recipient to circumstances where the donor has already been determined to have died, ruling out inclusion of potential circulatory death donors. An important difference in the IRI experienced in this study and that relevant to clinical transplantation is temperature—in conventional deceased-donor kidney transplantation, the majority of the ischemic time is hypothermic, rather than normothermic—and the effect that this difference has on the mechanism described here will need to be examined. The metabolomic changes described by the authors are intriguing, and it may be possible to look for similar signatures in human patients treated with SGLT2 inhibitors using MRI-based metabolic imaging techniques.9 Finally, normothermic machine perfusion (NMP) is an emerging technique that provides a platform on which the kidney can be treated ex situ, before it is transplanted.10 One of the advantages of this approach over donor treatment is that there is no ethical barrier to the inclusion of organs from circulatory death donors. SGLT inhibition and modulation of adenosine signaling during NMP may be approaches worth investigating. However, little is known about the safety, pharmacology, and efficacy of drug treatment during NMP. Intravenous formulations are required, and initial dose-escalation studies are likely to be necessary to evaluate safety and therapeutic potential. Yamanoi et al have uncovered a mechanism by which SGLT2 inhibition can reduce AKI that is intriguing and potentially highly relevant to kidney transplantation. There remains much work to be done to delineate how best to translate this work to the clinic.